Burimamide (IIa) was the first clinically effective H.sub.2 -receptor antagonist. It inhibits gastric secretion in animals, including man, but oral absorption is poor. ##STR5## Metiamide (IIb), a subsequently evaluated H.sub.2 -antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc) is as effective an H.sub.2 -antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug.
Reviews on the development of H.sub.2 -antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976) and in references cited therein.
U.S. Pat. No. 4,062,863 discloses histamine H.sub.2 -antagonists of the formula ##STR6## wherein R is hydrogen, (lower)alkyl or (CH.sub.2).sub.2 Z'CH.sub.2 -HET'; Z and Z' each are sulfur or methylene; and HET and HET' each are an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or an isothiazole ring, and pharmaceutically acceptable acid addition salts thereof. U.S. Pat. Nos. 4,120,968, 4,120,973 and 4,166,857 are divisionals thereof which have substantially the same disclosure.
U.K. Published Patent Application No. 2,023,133 discloses histamine H.sub.2 -antagonists of the formula ##STR7## wherein R.sub.1 and R.sub.2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, or R.sub.1 and R.sub.2, taken together with the nitrogen to which they are attached, may be a 5- to 10-membered alicyclic heterocyclic ring which may be saturated or may contain at least one double bond, which may be substituted by one or more alkyl groups or a hydroxy group and/or which may contain another heteroatom; Alk is a straight or branched alkylene chain of 1-6 carbon atoms; Q is a furan or thiophene ring incorporated into the molecule via the 2- and 5-positions, the furan ring optionally bearing a further substituent R.sub.7 adjacent the R.sub.1 R.sub.2 N-Alk- group, or Q is a benzene ring incorporated into the molecule via its 1- and 3- or 1- and 4-positions; R.sub.7 is halogen, alkyl (which may be substituted by hydroxy or alkoxy); X is methylene, oxygen, sulfur or &gt;N-R.sup.6 in which R.sup.6 is hydrogen or methyl; n is 0, 1 or 2; m is 2, 3 or 4; R.sub.3 is hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl having at least two carbon atoms, alkoxyalkyl or aryl; and R.sub.4 and R.sup.5 are independently hydrogen, alkyl, alkyl substituted by hydroxy or C.sub.1-3 alkoxy, alkenyl, aralkyl or heteroaralkyl, or R.sub.4 and R.sub.5 taken together with the nitrogen to which they are attached, may be a 5- to 7-membered saturated heterocyclic ring which may contain another heteroatom or the group &gt;NR.sup.6, or R.sub.4 and R.sub.5 taken together may be the group &gt;CR.sub.8 R.sub.9 wherein R.sub.8 is aryl or heteroaryl and R.sub.9 is hydrogen or alkyl; and physiologically acceptable salts and hydrates thereof.
Published European Patent Application No. 30,092 discloses histamine H.sub.2 -antagonists of the formula ##STR8## in which R.sup.1 and R.sup.2 are hydrogen or optionally halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl, provided that at least one of R.sup.1 and R.sup.2 is halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl;
X is a phenyl ring with 1 or 2 optional substituents or a 5- or 6-membered heterocyclic aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, the heterocyclic ring, where possible, having 1 optional substituent, which optional substituents are halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, hydroxy and amino; PA1 Y is O, S, a direct bond, methylene, cis or trans vinylene, sulfinyl or NR.sup.4 in which R.sup.4 is H or alkyl; PA1 m is 0 to 4 and n is 1 to 5; PA1 R.sup.3 is inter alia AB in which A is inter alia a 3,4-dioxocyclobuten-1,2-diyl radical and B is inter alia the radical NR.sup.7 R.sup.8 in which R.sup.7 and R.sup.8 are inter alia hydrogen, alkyl, haloalkyl, alkoxycarbonyl, alkenyl, alkynyl, (primary hydroxy)alkyl or (primary amino)alkyl, or R.sup.8 and R.sup.9, together with the nitrogen atom to which they are attached, may be a 5- or 6-membered ring which optionally contains O or NR.sup.9 in which R.sup.9 is H or alkyl. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; and PA1 A is ##STR11## in which R.sup.6 is hydrogen, (lower)alkyl, (lower)alkoxy or halogen; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen, (lower)alkyl, allyl, propargyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, cyclo(lower)alkyl, or phenyl(lower)alkyl, provided that R.sup.8 and R.sup.9 may not both be cyclo(lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane; PA1 or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; PA1 R.sup.6 is hydrogen or (lower)alkyl; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen or (lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane; PA1 or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; PA1 R.sup.6 is hydrogen or (lower)alkyl; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen or (lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane; PA1 or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; PA1 R.sup.6 is hydrogen or (lower)alkyl; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen or (lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane; PA1 or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; PA1 R.sup.6 is hydrogen or (lower)alkyl; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen or (lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane; PA1 or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (a) 1-Amino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (b) 1-Amino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4-dione hydrochloride. PA1 (c) 1-Amino-2-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}cyclobu tene-3,4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (d) 1-Amino-2-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}cyclo butene-3,4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (e) 1-Amino-2-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}cyclobut ene-3,4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (f) 1-Amino-2-[3-(3-dimethylaminomethylphenoxy)propylamino]cyclobutene-3,4-dio ne, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (g) 1-Amino-2-[3-(3-pyrrolidinomethylphenoxy)propylamino]cyclobutene-3,4-dione , or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (h) 1-Amino-2-{3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino}cyclobutene -3,4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (i) 1-Methylamino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4- dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (j) 2-[3-(3-Piperidinomethylphenoxy)propylamino]-1-(2-propnyamino)cyclobutene- 3,4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (k) 2-[3-(3-Piperidinomethylphenoxy)propylamino]-1-(3-pyridyl)methylaminocyclo butene-3,4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (l) 1-Amino-2-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (m) 1-Amino-2-[3-(3-piperidinomethylthiophenoxy)propylamino]cyclobutene-3,4-di one, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (n) 1-Amino-2-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]cyclobutene-3 ,4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 (o) 1-Amino-2-[3-(3-octamethyleneiminomethylphenoxy)propylamino]cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; and PA1 A is ##STR20## in which R.sup.6 is hydrogen, (lower)alkyl, (lower)alkoxy or halogen; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen, (lower)alkyl, allyl, propargyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, cyclo(lower)alkyl, or phenyl(lower)alkyl, provided that R.sup.8 and R.sup.9 may not both be cyclo(lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; PA1 R.sup.6 is hydrogen or (lower)alkyl; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen or (lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; PA1 R.sup.6 is hydrogen or (lower)alkyl; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen or (lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; PA1 R.sup.6 is hydrogen or (lower)alkyl; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen or (lower)alkyl, or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane. PA1 m is an integer of from 0 to 2 inclusive; PA1 n is an integer of from 2 to 5 inclusive; PA1 Z is sulfur, oxygen or methylene; PA1 R.sup.6 is hydrogen or (lower)alkyl; PA1 r is an integer of from 1 to 4 inclusive; and PA1 R.sup.8 and R.sup.9 each are independently hydrogen or (lower)alkyl; or R.sup.8 and R.sup.9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane. PA1 (a) 1-Methoxy-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4-dion e. PA1 (b) 1-Methoxy-2-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}cyclo butene-3,4-dione. PA1 (c) 1-Methoxy-2-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}cyc lobutene-3,4-dione. PA1 (d) 1-Methoxy-2-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}cyclob utene-3,4-dione. PA1 (e) 1-Methoxy-2-[3-(3-dimethylaminomethylphenoxy)propylamino]cyclobutene-3,4-d ione. PA1 (f) 1-Methoxy-2-[3-(3-pyrrolidinomethylphenoxy)propylamino]cyclobutene-3,4-dio ne. PA1 (g) 1-Methoxy-2-{3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino}cyclobute ne-3,4-dione. PA1 (h) 1-Methoxy-2-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]cyclobutene- 3,4-dione. PA1 (i) 1-Methoxy-2-[3-(3-piperidinomethylthiophenoxy)propylamino]cyclobutene-3,4- dione. PA1 (j) 1-Methoxy-2-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]cyclobutene -3,4-dione. PA1 (k) 1-Methoxy-2-[3-(3-octamethyleneiminomethylphenoxy)propylamino]cyclobutene- 3,4-dione. PA1 (a) 3-(3-pyrrolidinomethylphenoxy)propylamine, PA1 (b) 3-[3-(2-methylpyrrolidino)methylphenoxy]propylamine, PA1 (c) 3-[3-(3-methylpyrrolidino)methylphenoxy]propylamine, PA1 (d) 3-[3-(4-methylpiperidino)methylphenoxy]propylamine, PA1 (e) 3-(3-morpholinomethylphenoxy)propylamine, PA1 (f) 3-[3-(4-hydroxypiperidino)methylphenoxy]propylamine, PA1 (g) 3-[3-(N-methylpiperazino)methylphenoxy]propylamine, PA1 (h) 3-[3-(1,2,3,6-tetrahydro-1-pyridyl)methylphenoxy]propylamine, PA1 (i) 3-(3-hexamethyleneiminomethylphenoxy)propylamine, PA1 (j) 3-(3-heptamethyleneiminomethylphenoxy)propylamine, PA1 (k) 4-(3-piperidinomethylphenoxy)butylamine, PA1 (l) 5-(3-piperidinomethylphenoxy)pentylamine, PA1 (m) 3-(3-octamethyleneiminomethylphenoxy)propylamine, PA1 (n) 3-[3-(3-azabicyclo[3.2.2]non-3-yl)methylphenoxy]propylamine and PA1 (o) 3-[3-(3-pyrrolino)methylphenoxy)propylamine, respectively, PA1 (a) 1-amino-2-[3-(3-pyrrolidinomethylphenoxy)propylamino]cyclobutene-3,4-dione as its hydrochloride salt, m.p. 192.5-195.degree.. PA1 (b) 1-amino-2-3-[3-(2-methylpyrrolidino)methylphenoxy]propylaminocyclobutene-3 ,4-dione as its hydrochloride salt, m.p. 210-212.degree.. PA1 Anal. Calc'd for C.sub.19 H.sub.25 N.sub.3 O.sub.3 HCl: C, 60.08; H, 6.90; N, 11.06; Cl, 9.33 Found: C, 59.97; H, 6.92; N, 10.88; Cl, 9.46 PA1 (c) 1-amino-2-{3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino}cyclobutene -3,4-dione as its hydrochloride salt, m.p. 184.5-187.degree.. PA1 (d) 1-amino-2-{3-[3-(4-methylpiperidino)methylphenoxy]propylamino}cyclobutene- 3,4-dione, PA1 (e) 1-amino-2-[3-(3-morpholinomethylphenoxy)propylamino]cyclobutene-3,4-dione, PA1 (f) 1-amino-2-{3-[3-(4-hydroxypiperidino)methylphenoxy]propylamino}cyclobutene -3,4-dione, PA1 (g) 1-amino-2-{3-[3-(N-methylpiperazino)methylphenoxy]propylamino}cyclobutene- 3,4-dione, PA1 (h) 1-amino-2-{3-[3-(1,2,3,6-tetrahydro-1-pyridyl)methylphenoxy]propylamino}cy clobutene-3,4-dione, m.p. 213-215.degree. (dec.), PA1 (i) 1-amino-2-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]cyclobutene-3, 4-dione as its hydrochloride salt, m.p. 200.degree.-202.degree.. PA1 (j) 1-amino-2-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]cyclobutene-3 ,4-dione, m.p. undefined, gradual decomposition.about.200.degree.-240.degree.. PA1 (k) 1-amino-2-[4-(3-piperidinomethylphenoxy)butylamino]cyclobutene-3,4-dione, PA1 (1) 1-amino-2-[5-(3-piperidinomethylphenoxy)pentylamino]cyclobutene-3,4-dione, (m) 1-amino-2-[3-(3-octamethyleneiminomethylphenoxy)propylamino]cyclobutene-3, 4-dione, m.p. undefined. PA1 (n) 1-amino-2-{3-[3-(3-azabicyclo[3.2.2]non-3-yl)methylphenoxy]propylamino}cyc lobutene-3,4-dione as its hydrochloride salt, m.p. 162-164.degree. and PA1 (o) 1-amino-2-{3-[3-(3-pyrrolino)methylphenoxy]propylamino}cyclobutene-3,4-dio ne, respectively. PA1 (a) ethylamine, PA1 (b) n-butylamine, PA1 (c) allylamine, PA1 (d) propargylamine, PA1 (e) benzylamine and PA1 (f) 6-methyl-3-aminomethylpyridine, respectively, PA1 (a) 1-ethylamino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4-d ione, (b) 1-butylamino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4-d ione, (c) 1-allylamino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4-d ione, m.p. 158.degree.-159.5.degree.. PA1 (d) 2-[3-(3-piperidinomethylphenoxy)propylamino]-1-(2-propynylamino)cyclobuten e-3,4-dione, m.p. 158.degree.-160.degree.. PA1 (e) 1-benzylamino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4- dione hydrochloride, m.p. 136.degree.-140.degree..